EP1089710A1 - Formulations pharmaceutiques injectables de derives de la partricine - Google Patents
Formulations pharmaceutiques injectables de derives de la partricineInfo
- Publication number
- EP1089710A1 EP1089710A1 EP99914507A EP99914507A EP1089710A1 EP 1089710 A1 EP1089710 A1 EP 1089710A1 EP 99914507 A EP99914507 A EP 99914507A EP 99914507 A EP99914507 A EP 99914507A EP 1089710 A1 EP1089710 A1 EP 1089710A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formulation according
- partricin
- derivative
- lipid
- emulsion
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- NVJUPMZQNWDHTL-MJODAWFJSA-N partricin Chemical class O1C(=O)CC(O)CC(=O)CC(O)CC(O)CC(O)CC(O)CC(O2)(O)CC(O)C(C(O)=O)C2CC(O[C@@H]2[C@@H]([C@H](N)[C@@H](O)[C@H](C)O2)O)\C=C\C=C\C=C\C=C\C=C\C=C\C=C\C(C)C1C(C)CCC(O)CC(=O)C1=CC=C(N)C=C1 NVJUPMZQNWDHTL-MJODAWFJSA-N 0.000 title claims abstract description 56
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 7
- 239000000203 mixture Substances 0.000 claims abstract description 82
- 238000009472 formulation Methods 0.000 claims abstract description 63
- 150000002632 lipids Chemical class 0.000 claims abstract description 43
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 32
- 239000000839 emulsion Substances 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000012458 free base Substances 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 9
- 238000011282 treatment Methods 0.000 claims abstract description 7
- 230000003381 solubilizing effect Effects 0.000 claims abstract description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 27
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 15
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 15
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 14
- 239000008103 glucose Substances 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
- 239000002245 particle Substances 0.000 claims description 10
- 244000068988 Glycine max Species 0.000 claims description 9
- 235000010469 Glycine max Nutrition 0.000 claims description 9
- 239000002671 adjuvant Substances 0.000 claims description 9
- 235000011187 glycerol Nutrition 0.000 claims description 9
- 150000001408 amides Chemical class 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 230000001954 sterilising effect Effects 0.000 claims description 8
- 239000000725 suspension Substances 0.000 claims description 8
- 241001465754 Metazoa Species 0.000 claims description 7
- 235000010323 ascorbic acid Nutrition 0.000 claims description 7
- 229960005070 ascorbic acid Drugs 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- -1 alkyl paraben Chemical compound 0.000 claims description 6
- 239000011668 ascorbic acid Substances 0.000 claims description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 235000013311 vegetables Nutrition 0.000 claims description 6
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 5
- 238000004659 sterilization and disinfection Methods 0.000 claims description 5
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 4
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 239000006184 cosolvent Substances 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 239000002077 nanosphere Substances 0.000 claims description 4
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- 229920000136 polysorbate Polymers 0.000 claims description 4
- 239000004094 surface-active agent Substances 0.000 claims description 4
- 150000003626 triacylglycerols Chemical class 0.000 claims description 4
- PILBMRSRDPAALN-OUXUIHJTSA-N (4e,6e,8e,10e,12e,14e,16e)-3-[(2s,3r,4r,5r,6s)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-23,27,29,31,33,35,37-heptahydroxy-19-[5-hydroxy-7-[4-(methylamino)phenyl]-7-oxoheptan-2-yl]-18-methyl-21,25-dioxo-20,39-dioxabicyclo[33.3.1]nonatriaconta-4,6,8,10,1 Chemical class C1=CC(NC)=CC=C1C(=O)CC(O)CCC(C)C1C(C)/C=C/C=C/C=C/C=C/C=C/C=C/C=C/C(O[C@@H]2[C@@H]([C@H](N)[C@@H](O)[C@H](C)O2)O)CC(O2)C(C(O)=O)C(O)CC2(O)CC(O)CC(O)CC(O)CC(O)CC(=O)CC(O)CC(=O)O1 PILBMRSRDPAALN-OUXUIHJTSA-N 0.000 claims description 3
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 3
- GIPOAAKKTPTFIB-ZZMNMWMASA-N CN(C)CCN.OC[C@@H]([C@H](C(O)=C1O)OC1=O)O.OC[C@@H]([C@H](C(O)=C1O)OC1=O)O Chemical compound CN(C)CCN.OC[C@@H]([C@H](C(O)=C1O)OC1=O)O.OC[C@@H]([C@H](C(O)=C1O)OC1=O)O GIPOAAKKTPTFIB-ZZMNMWMASA-N 0.000 claims description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 229930182558 Sterol Natural products 0.000 claims description 3
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims description 3
- 235000006708 antioxidants Nutrition 0.000 claims description 3
- 239000000872 buffer Substances 0.000 claims description 3
- 235000012000 cholesterol Nutrition 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 229960003964 deoxycholic acid Drugs 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000004108 freeze drying Methods 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 3
- DTSSDPFTHGBSDX-KVTDHHQDSA-N mycosamine Chemical compound C[C@@H](O)[C@@H](O)[C@H](N)[C@H](O)C=O DTSSDPFTHGBSDX-KVTDHHQDSA-N 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 238000000527 sonication Methods 0.000 claims description 3
- 229940083466 soybean lecithin Drugs 0.000 claims description 3
- 150000003432 sterols Chemical class 0.000 claims description 3
- 235000003702 sterols Nutrition 0.000 claims description 3
- 239000000811 xylitol Substances 0.000 claims description 3
- 235000010447 xylitol Nutrition 0.000 claims description 3
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 3
- 229960002675 xylitol Drugs 0.000 claims description 3
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 2
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930003427 Vitamin E Natural products 0.000 claims description 2
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 2
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- 238000001035 drying Methods 0.000 claims description 2
- 229940013317 fish oils Drugs 0.000 claims description 2
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 2
- 239000002563 ionic surfactant Substances 0.000 claims description 2
- 239000002736 nonionic surfactant Substances 0.000 claims description 2
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- 235000021317 phosphate Nutrition 0.000 claims description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 2
- 150000003905 phosphatidylinositols Chemical class 0.000 claims description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 2
- 239000008389 polyethoxylated castor oil Substances 0.000 claims description 2
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- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 2
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- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 claims 1
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- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims 1
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- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
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- 239000008188 pellet Substances 0.000 description 1
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- 238000012545 processing Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
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- 239000012086 standard solution Substances 0.000 description 1
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
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- Y10S977/00—Nanotechnology
- Y10S977/70—Nanostructure
- Y10S977/788—Of specified organic or carbon-based composition
- Y10S977/797—Lipid particle
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y10S977/70—Nanostructure
- Y10S977/788—Of specified organic or carbon-based composition
- Y10S977/797—Lipid particle
- Y10S977/798—Lipid particle having internalized material
- Y10S977/799—Containing biological material
- Y10S977/801—Drug
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/905—Specially adapted for travel through blood circulatory system
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/906—Drug delivery
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/926—Topical chemical, e.g. cosmetic or sunscreen
Definitions
- This invention relates to new injectable pharmaceutical formulations containing partricin derivatives as the active ingredient.
- the new pharmaceutical formulations enclose at least one derivative of partricin in the form of a free base, or a pharmaceutically acceptable water-soluble salt of it, in a solubilizing/dispersing medium made up of a lipid and/or phospholipid emulsion in water.
- the afore-said documents also describe the preparation of their salts with acids, acceptable from a pharmacological and pharmaceutical point of view, and report that such salts are unusually water-soluble. It has already been ascertained that the partricin derivatives, described in the afore-said European patent applications, can also be used in clinical practice, for human and veterinary application as drugs for treatment of several pathologies sensitive to the partricin derivatives; in particular, injectable formulations may be prepared enclosing such derivatives, evidencing the advantages deriving from the water-solubility of the said partricin derivatives.
- formulations may permit, for instance, using a derivative of partricin' s as the active ingredient (e.g., N-dimethylaminoacetyl-partricin A 2-dimethylamino- ethylamide diascorbate - code name SPA-S-843) for instance with the addition of ascorbic acid, as antioxidant, and of lactose as excipient.
- a derivative of partricin' s as the active ingredient
- the freeze-dried product is normally dissolved in 5% glucose solution at the time of use and administered by slow intravenous infusion.
- One of the subjects of the present invention is in fact an injectable pharmaceutical formulation enclosing at least one partricin derivative in the form of free base - or of water-soluble pharmaceutically acceptable salt thereof, with acids that are acceptable from a pharmaceutical and pharmacological point of view - in a solubilizing/dispersing medium made up of a lipid and/or phospholipid emulsion in water such that the resulting emulsion be iso-osmotic.
- the expression "partricin derivative” indicates the derivatives of partricin described in patent applications EP-A-0434943, EP-A-0489308, GB-A- 1359473 (equivalent to US 3780173) and GB-A-1046774 (equivalent to US 3961047).
- preferred formulations are those wherein the partricin derivative is a derivative of partricin A and/or B presenting the carboxyl in position C18 of the macrolidic ring in the form of ester or of neutral amide or of amide containing a basic nitrogen group in the side chain, and those wherein the derivative is further substituted, on the primary amino group of mycosamine in the form of amide with an acid containinga basic nitrogen group in the side chain.
- a partricin derivative specially preferred for the formulations of the invention is N- dimethylaminoacetyl-partricin A 2-dimethylamino-ethylamide.
- the formulations of the invention enclose a partricin derivative in the form of a free base
- a surfactant and/or a co-solvent is preferred in order to avoid any eventual problem of active ingredient solubilization before its inclusion in the lipid emulsion; alternatively, this trouble can be avoided by sonication of the particles, elevation of the system temperature e.g., from room temperature to 40-50°C, and etc..
- these salts are preferably formed with at least one, preferably two, acid equivalents, preferably ascorbic or aspar.tic acid; the salt preferred for the formulations of the invention is N-dimethylaminoacetyl-partricin A 2- dimethylamino-ethylamide diascorbate, as such or as its free base.
- the formulations of the invention comprise a pharmaceutically effective quantity of the partricin derivative; the dose of partricin derivative per unit to be administered remains substantially equal to that of the traditional formulations. In particular, the quantity ranges from 1 to 100 mg, preferably 10 to 50 mg.
- the partricin derivative enclosed in the formulations of the invention is, preferably, in the form of solution, of micellar pseudosolution, of encapsulated inclusion compound, or of suspension of sub-micronized particles, their size being smaller than 5 ⁇ m, preferably smaller or equal to 3 ⁇ m, to avert the risk of pulmonary embolism; following sterilization (by sterilizing filtration or other suitable method) , the partricin derivative can directly be added to the lipid emulsion or, preferably, stored in the dry state, following suitable processing (e.g., through freeze-drying) , to improve long-term stability and be added to the lipid emulsion just prior to its therapeutic use by parenteral injection, particularly intravasal and, preferably, intravenous route .
- suitable processing e.g., through freeze-drying
- the solubilizing/dispersing medium is a lipid emulsion, preferably oil-in-water, containing lipids and/or phospholipids, in the form of droplets, vesicles, nanospheres , etc .
- the lipids and/or phospholipids used in the formulations of the present invention can be from different origin, that is, animal and/or vegetable and/or synthetic and/or semisynthetic origin (hydrogenated fats and the like).
- the lipids are preferably taken from the group of the mono-, di- or triglycerides; specially triglycerides; when of vegetable origin preferably from olives, for instance triolein, or from soybeans, when of animal origin preferably fish oils.
- the phospholipids, in particular the phosphatidylcholines, when of vegetable origin are typically soybean lecithins, when of animal origin are selected preferably from egg yolk lecithins .
- phospholipids preferred for the formulations of the invention, are those selected from the group of the distearoilphosphatidyl-choline, dimyristoilphosphatidylcholine, dimyristoilphosphatidylglycerol, phosphatidyl-ethanolamine, phosphatidylserine , phosphatidyl-inositol . Hydrogenate lipids and/or phospholipids too can be used in the formulations of the invention.
- phospholipids When phospholipids are used alone, they can be in the form of multilamellar or unilamellar, large or small vesicles, optionally containing sterols. In other cases, lipids and/or phospholipids can be present in the form of lipid nanospheres able to encapsulate the partricin derivative.
- the concentration of the lipids eventually present in the formulations of the invention varies from 1 to 25%, being it usually 10-20% while the concentration of the phospholipids eventually present can vary from 0.05% to 5%.
- the formulations of the invention can also enclose an excipient and/or a pharmaceutically acceptable adjuvant, such as those commonly used in the formulations intended for injectable use and according to the evidence of the experts in the field, for instance selected from the sugar group, preferably lactose, glucose, saccharose, maltose; antioxidants , preferably ascorbic acid, sodium ascorbate, vitamin E; preservatives, preferably alkyl paraben, benzyl alcohol; ionic or non-ionic surfactants, preferably sodium laurylsulfate, sodium deoxycholate, Tween ® , particularly Tween 80, polysorbates, Cremophor (LE or other); acid or neutral or basic buffers, preferably mono- or bi-basic phosphates; co-solvents;
- the formulations of the invention can moreover be realized in both a pharmaceutical form wherein the partricin derivative is already inserted in the lipid and/or phospholipid emulsion together with any eventual excipient and/or adjuvant, and in a pharmaceutical form wherein the partricin derivative is preserved in an anhydrous state (in the form, for instance, of a lyophile), together with any eventual excipient and/or adjuvant, separated from the lipid and/or phospholipid emulsion, together with any eventual excipient and/or adjuvant, in which it is extempore inserted before therapeutic administration.
- the formulations of the invention are useful to prepare a medicament intended for the clinical treatment of pathologies sensitive to the action of the partricin derivative, such as, f.i., those described in EP-A-0434943, EP-A-0489308, GB- A-1359473 and GB-A-1046774 and several other pathologies.
- the texts of the four a/m documents are incorporated, for reference, in the present description, in particular as regards the partricin derivatives, their preparations and their described uses . All the above mentioned products (lipids, phospholipids, excipients etc.) are commercially available and must be specially purified, fractioned and declared suitable for the injectable use (non pyrogenic etc.)
- the final composition should be such as to conduct to an iso- osmotic emulsion.
- Industrial preparation of the emulsions requires the use of special equipment such as, in example, colloidal mills, two- stage pressure homogenizers , ultrasound generators, as is evident to an expert in the sector. Special attention will have to be paid to size control of the particles in suspension (sub-micron dimensions or, at any rate, not greater than 3-5 ⁇ m) , to their distribution interval and their homogeneity, as well as stability of the emulsion itself, as is evident to an expert of the sector.
- An additional item of the present invention consists in a procedure for preparation of the formulations of the invention, comprising sterilization - preferably by sterilizing filtration of the solution, micellar pseudo- solution, encapsulated compound or suspension of sub- micronized particles of the partricin derivative -and subsequent inclusion in the lipid and/or phospholipid emulsion.
- drying of the derivative is preferred - subsequent to sterilization and, at any rate, before inclusion in the lipid and/or phospholipid emulsion, of the solution, pseudo- solution or suspension of the partricin derivative preferably through freeze-drying.
- the procedure according to the invention can also comprise the addition of a surface active agent and/or a co- solvent to the partricin derivative or sonication of the particles or rising of the system temperature, passing, i.e., from room temperature to 40°-50°C, before inclusion of the derivative into the lipid and/or phospholipid emulsion.
- Incorporation of the drug in the lipid emulsion can occur in both the presence of the partricin derivative in the form of a solution, and in the solid state: in the latter case, the solid, for example a freeze-dried substance, can first be dissolved or dispersed in sterile water and the solution added to the emulsion or, better still, it can be directly solubilized with a portion of it. The final preparation will be sterile.
- the final volume of the injectable formulation of the invention varies, in general from 5-10 ml when intended for bolus administration, to 100, 250, 500 ml when intended for slow, drip infusion over 1-5 hours, as evident to an expert of the sector.
- the formulations of the invention can unexpectedly reduce and even eliminate, the local irritating effects when used by intravascular route, contrary to what commonly occurs when using more traditional formulations as those obtained in glucose solution (5% glucose solution) or in physiological solution (0.9% sodium chloride solution).
- the formulations of the invention allow, for instance, incorporation of the more lipophylic (hydrophobic) derivatives of partricin, in particular if in the form of free bases, in the inner oily phase of the oil-in-water emulsion, enabling the derivatives to be released over longer times and with particular tropism for the cells of the reticuloendothelial system and for the organs rich thereof, with relative decrease of the blood levels and wide changes of their toxicity.
- ampoule A The solution in ampoule A is freeze-dried and before use the solid residue re-dissolved with the diluent from ampoule B; the resulting mixture is slowly injected as a bolus dose, by intravenous route .
- the mixture of sterile powders in ampoule A is dissolved with a portion (5-10 ml) of diluent from vial B; the mixture is then transferred, under sterile conditions, to vial B, corrected to about pH 7.5 with sterile phosphate buffer if necessary, and injected by slow intravenous infusion over 1 hour.
- Example 4 Ampoule A - Active ingredient (see Example 2)
- Example 5 Ampoule A - Active ingredient (see Example 2)
- the content of ampoule A is treated with the diluent from vial B and administered by slow intravenous infusion, as indicated in Example 3.
- Soybean lipids 10 g Soybean phospholipids
- the active ingredient in ampoule A is treated with the diluent from vial B and administered as described in example
- the mixture pH 5.5, is slowly injected by intravenous route as a bolus dose.
- An injectable preparation of active ingredient (ampoule A - 50 mg of SPA-S-843) in 100 ml of a lipid emulsion (vial B) having the composition reported in Example 3 and obtained with the procedure as in the same Example 3, was compared for local tolerance with a formulation obtained by dissolving the content of another ampoule A, same as before, in 100 ml of 5% glucose standard solution. Both formulations (lipid and glucose) contained 0.5 mg of SPA-S-843/ml .
- the tests were carried out in five adult male New Zealand albino rabbits weighing 2.8+0.2 kg, by daily injecting intravenously, over a time of 120 seconds, 2 ml in total (1 mg of £)PA ⁇ -S ⁇ 843) of both lipid and glucose solutions intp the marginal veins of the left and right ear respectively. This treatment was repeated for 3 or more days.
- Example 12 The same lipid formulation as described in Example 12 was tested in the same experimental model by protracting the number of administrations into the rabbit ear marginal vein.
- the SPA-S-843 lipid formulation substantially confirmed the substantial absence of local reactions and the superiority in comparison with standard injectable formulations.
- SPA-S-843 free base was dissolved under nitrogen in a mixture of methylene chloride :methanol in the ratio 9:1 (1 mg/ml) and mixed with an equal volume of a methylene chloride solution of phospholipids (hydrogenated phosphatidylcholine and distearoyl phosphatidyl-choline) and with a methanol: ethylene chloride solution of cholesterol, so as to give a molar ratio of drug to lipids of 1:5:2:2.5, and the solvents were removed under reduced pressure.
- the phospholipids were represented, for instance, by egg lecithin alone.
- the dried drug-phospholipid film was suspended in a standard phosphate-saline buffer (PSB) and hand-shaken allowing the film to form lipidic vescicles.
- PSB standard phosphate-saline buffer
- the suspension was centrifuged for 1 hour and the pellet was additioned with maltose in the ratio 1:1 (w/w) and lyophilized.
- the resulting mixture is injected by slow intravenous infusion over 1 hour .
- the i.v. 50% lethal dose (LD so ) of the SPA-S-843 formulation, obtained according to Example 15, is increased from 70 mg/kg to >200 mg/kg
- Example 16 A mixture of 25 mg of SPA-S-843, f.i. in the form of free base, 2.5 g of soybean oil and 2.5 g of egg-lecithin is treated with water under stirring to give an emulsion, the mixture is added with 5 g of maltose while stirring and preserved as a lyophilized formulation. After reconstitution with sterile distilled water, just before the use, the active ingredient is present as lipid nanosphere - encapsulated particles, having an average size of 25 to 50 nm.
- the mixture is then diluted with 5% dextrose to the desired concentration, usually to 100 ml, to be injected by slow infusion within 1 hour by i.v. route.
- the formulation shows a good distribution to sites of infection and low uptake by reticuloendothelial system.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Biophysics (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Communicable Diseases (AREA)
- Dispersion Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Hydrogenated Pyridines (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK99914507T DK1089710T3 (da) | 1998-06-25 | 1999-03-11 | Injicerbare farmaceutiske formuleringer af partricinderivater |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI981457 | 1998-06-25 | ||
IT1998MI001457A IT1301807B1 (it) | 1998-06-25 | 1998-06-25 | Formulazioni farmaceutiche iniettabili di derivati della partricina. |
PCT/EP1999/001571 WO1999066902A1 (fr) | 1998-06-25 | 1999-03-11 | Formulations pharmaceutiques injectables de derives de la partricine |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1089710A1 true EP1089710A1 (fr) | 2001-04-11 |
EP1089710B1 EP1089710B1 (fr) | 2005-08-10 |
Family
ID=11380320
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99914507A Expired - Lifetime EP1089710B1 (fr) | 1998-06-25 | 1999-03-11 | Formulations pharmaceutiques injectables de derives de la partricine |
Country Status (11)
Country | Link |
---|---|
US (1) | US6586407B1 (fr) |
EP (1) | EP1089710B1 (fr) |
JP (1) | JP4719355B2 (fr) |
KR (1) | KR100622290B1 (fr) |
AT (1) | ATE301453T1 (fr) |
DE (1) | DE69926633T2 (fr) |
DK (1) | DK1089710T3 (fr) |
ES (1) | ES2245096T3 (fr) |
IT (1) | IT1301807B1 (fr) |
PT (1) | PT1089710E (fr) |
WO (1) | WO1999066902A1 (fr) |
Families Citing this family (4)
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PT2627173E (pt) | 2010-10-12 | 2015-07-24 | Medicines Co | Formulações de clevidipina em emulsão contendo agentes antimicrobianos |
US8658676B2 (en) | 2010-10-12 | 2014-02-25 | The Medicines Company | Clevidipine emulsion formulations containing antimicrobial agents |
CN111867562B (zh) * | 2018-03-07 | 2023-07-07 | 陈献 | 不溶性药物的水性制剂 |
WO2023285323A2 (fr) * | 2021-07-12 | 2023-01-19 | Bioseutica B.V. | Procédé de production d'amcipatricine diascorbate et son utilisation pour le traitement d'infections fongiques invasives résistantes aux agents antifongiques classiques |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1359473A (en) * | 1970-11-03 | 1974-07-10 | Prodotti Antibiotici Spa | Polyenic antibiotic |
GB1406774A (en) * | 1973-02-15 | 1975-09-17 | Prodotti Antibiotici Spa | Esters of patricin and of partricin derivatives |
GB1413256A (en) * | 1973-05-14 | 1975-11-12 | Prodotti Antibiotici Spa | Water-solubilised antibiotics |
GB1463348A (en) * | 1974-09-03 | 1977-02-02 | Prodotti Antibiotici Spa | Water-solubilised compositions |
IE60901B1 (en) * | 1986-08-21 | 1994-08-24 | Vestar Inc | Improved treatment of systemic fungal infections with phospholipid particles encapsulating polyene antifungal antibiotics |
JP2653245B2 (ja) * | 1989-11-27 | 1997-09-17 | 日本新薬株式会社 | 脂肪乳剤 |
JP2830243B2 (ja) * | 1989-12-21 | 1998-12-02 | 味の素株式会社 | ポリエン含有組成物 |
IT1243404B (it) * | 1990-12-03 | 1994-06-10 | Prodotti Antibiotici Spa | Derivati della partricina |
IT1283149B1 (it) * | 1996-07-12 | 1998-04-07 | Prodotti Antibiotici Spa | Complessi di n'-dimetilaminoacetilpartricina a dimetilaminoetilamide, o suoi sali, e colesterol 3-solfato |
-
1998
- 1998-06-25 IT IT1998MI001457A patent/IT1301807B1/it active IP Right Grant
-
1999
- 1999-03-11 KR KR1020007014665A patent/KR100622290B1/ko not_active IP Right Cessation
- 1999-03-11 US US09/720,236 patent/US6586407B1/en not_active Expired - Lifetime
- 1999-03-11 DE DE69926633T patent/DE69926633T2/de not_active Expired - Lifetime
- 1999-03-11 ES ES99914507T patent/ES2245096T3/es not_active Expired - Lifetime
- 1999-03-11 AT AT99914507T patent/ATE301453T1/de active
- 1999-03-11 JP JP2000555588A patent/JP4719355B2/ja not_active Expired - Fee Related
- 1999-03-11 DK DK99914507T patent/DK1089710T3/da active
- 1999-03-11 EP EP99914507A patent/EP1089710B1/fr not_active Expired - Lifetime
- 1999-03-11 WO PCT/EP1999/001571 patent/WO1999066902A1/fr active IP Right Grant
- 1999-03-11 PT PT99914507T patent/PT1089710E/pt unknown
Non-Patent Citations (1)
Title |
---|
See references of WO9966902A1 * |
Also Published As
Publication number | Publication date |
---|---|
ES2245096T3 (es) | 2005-12-16 |
JP4719355B2 (ja) | 2011-07-06 |
DE69926633T2 (de) | 2006-05-18 |
KR20010071581A (fr) | 2001-07-28 |
ITMI981457A1 (it) | 1999-12-25 |
PT1089710E (pt) | 2005-11-30 |
ATE301453T1 (de) | 2005-08-15 |
US6586407B1 (en) | 2003-07-01 |
WO1999066902A8 (fr) | 2001-02-15 |
DE69926633D1 (de) | 2005-09-15 |
EP1089710B1 (fr) | 2005-08-10 |
WO1999066902A1 (fr) | 1999-12-29 |
IT1301807B1 (it) | 2000-07-07 |
DK1089710T3 (da) | 2005-10-17 |
JP2002518431A (ja) | 2002-06-25 |
KR100622290B1 (ko) | 2006-09-11 |
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